Whole mount of adult ear skin as a model to study vascular malformations.
Whole mount of adult ear skin as a model to study vascular malformations.
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DOI：
10.1002/ame2.12343
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发表时间：
2023-08
影响因子：
3.7
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中科院分区：
文献类型：
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对人类患者的遗传分析表明，PI-3‘Kinase的催化亚单位PIK3CA的突变与零星发生的血管畸形有关。我们已经建立了一种可诱导和内皮特异性表达PIK3CAH1047R的小鼠模型，导致血管畸形的发生。在成年小鼠中全身诱导这种突变会导致快速死亡，限制了我们跟踪和研究这些病变的能力；因此，我们开发了一种使用他莫昔芬的活性代谢物4OH-T在成人耳部皮肤上局部诱导的局部诱导方案。这种方法使我们能够在成熟和已建立的血管床上成功地模拟人类疾病，并跟踪血管畸形的发展。为了验证这个模型的实用性，我们应用了局部雷帕霉素软膏，因为在临床试验中，雷帕霉素对患者的治疗是有益的。我们发现，治疗后诱发的耳部病变明显减弱，这一点很容易量化。这些数据共同提供了研究成人组织中血管畸形的新模型的证据，这在缺乏专门的小动物成像设备的环境中应该特别有用。4耳涂片和成人耳皮肤整装为观察和研究PIK3CAH1047R 驱动的血管畸形的分子基础提供了局部的、可追踪的和可重现的模型。该模型绕过了与系统诱导方案相关的许多复杂性，并允许直接可视化血管畸形的发展。
Genetic analysis in human patients has linked mutations in PIK3CA, the catalytic subunit of PI‐3′Kinase, to sporadic incidences of vascular malformations. We have developed a mouse model with inducible and endothelial‐specific expression of PIK3CAH1047R, resulting in the development of vascular malformations. Systemic induction of this mutation in adult mice results in rapid lethality, limiting our ability to track and study these lesions; therefore, we developed a topical and local induction protocol using the active metabolite of tamoxifen, 4OH‐T, on the ear skin of adults. This approach allows us to successfully model the human disease in a mature and established vascular bed and track the development of vascular malformations. To validate the utility of this model, we applied a topical rapamycin ointment, as rapamycin is therapeutically beneficial to patients in clinical trials. We found that the induced ear lesions showed significant attenuation after treatment, which was easily quantified. These data collectively provide evidence of a new model to study vascular malformations in adult tissues, which should be particularly useful in environments lacking specialized small‐animal imaging facilities. 4OHT ear painting and whole mount of adult ear skin provides local, traceable, and reproducible model for observing and investigating the molecular underpinnings of PIK3CAH1047R driven vascular malformations. This model circumvents many of the complexities associated with systemic induction protocols and allows for direct visualization of the development of vascular malformations.
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